Heparan sulfate (HS) binds and functionally modulates a number of growth factors and morphogens. Genetic studies have revealed that HS is an integral component of many developmental signaling pathways in model animals. However, our understanding of the role of HS in the mammalian skeletal development and remodeling is still quite limited, and this is in spite of the fact that the tissue most affected by aberrant expression of HS is bone. For example, mutations of the gene encoding an enzyme essential for HS synthesis cause Hereditary Multiple Exostosis (HME), which is one of the most common genetic bone disorders in clinical orthopedics. In the adults, long-term heparin treatment for patients with thromboembolism and other vascular diseases often leads to a low bone mass condition resembling osteoporosis. The improved understanding of the mechanisms by which HS regulates growth factor signaling in the developing and adult skeletal system is critical for devising therapies for these diseases. Toward this long- term goal, we have employed conditional mouse genetics approaches to dissect the function of HS in skeletal development and physiology. Our evidence suggests that HS is essential for normal skeletal patterning and skeletal cell differentiation, being involved in key growth factor signaling pathways. Based on these and other preliminary data, we propose the following specific aims: 1. To dissect time-dependence and structural specificity of HS function in chondrogenesis. 2. To determine the mechanisms by which HS regulates BMP function during chondrogenesis. 3. To determine the role of HS in developmental bone formation and the regulation of bone mass. The proposed studies will generate new insights into the pathogenesis of HME, and may help define new drug targets for osteoporosis. PUBLIC HEALTH RELEVANCE: Heparan sulfate is essential for normal bone development and physiology, as illustrated by the existence of the genetic (hereditary multiple exostosis) and metabolic (heparin- induced osteoporosis) bone diseases that are directly linked to aberrant expression of heparan sulfate. This project will employ advanced mouse genetics to elucidate the molecular mechanisms by which heparan sulfate regulates bone cell function. The proposed studies will generate new insights into the pathogenesis of hereditary multiple exostosis, and may help define new drug targets for osteoporosis.